Gene therapy has drawn significant interest in the past two decades, since it is a promising strategy for the treatment of genetic disorders or acquired diseases that are currently considered incurable. The success of gene therapy relies on safe and efficient gene delivery systems. These systems must have following characteristics, DNA protection, cellular uptake, endosomal escape and low toxicity, to overcome obstacles in gene therapy. So far, various delivery systems have been developed, and they can be grouped into two categories: viral and non-viral vectors. Non-viral vectors are not as efficient as viral vectors, but provide safer delivery strategies since they could avoid the problems associated with viruses, including complexity of production, immunogenicity and mutagenesis. Currently, the majority of non-viral vectors are made of synthetic materials, such as cationic lipids, polymers, and dendrimers. Some of them could induce high gene transfection in vitro; however, many of these systems had high toxicity, low biodegradability and poor biocompatibility in vivo.
Natural materials, such as cationic polysaccharides and peptides, have been studied as potential gene delivery carriers to avoid the chronic toxicity associated with carriers based on synthetic materials. Chitosan has been intensively studied as the gene delivery carrier due to its biocompatibility, but its transfection efficiency is still unsatisfactory and the solubility at neutral condition is low. Peptide vectors, composed of natural amino acids, are compatible with biological environment, less cytotoxic and biodegradable. In addition, these vectors are adaptable to rational design since amino acid building blocks with diverse properties provide us the freedom for developing multifunctional drug carriers with the desired functions. For example, arginine residue which is positively charged in physiological environment has been used to condense negatively charged therapeutic DNA or RNA. Histidine residue is introduced into peptides to help DNA escape from endosome and thus to improve transfection efficiency. A previous study demonstrated that integrated peptides with ligand peptide sequence can achieve targeted gene delivery to the specific cells. However, the size of the peptide has to be over a certain value to accommodate all desired functions and it will dramatically increase the cost of the peptide.
In general, there have been three major obstacles for the further development of natural polymer-based gene carriers. Firstly, all of the reported gene drug vectors have provided only part of required functions, such as high transfection efficiency, long blood circulation and effective targeting properties. Secondly, the gene transfection efficiency of natural polymer in general has been low. Thirdly, drug loading efficiency of these natural polymer based carriers has also been low and thus optimal gene transfection is achieved at relatively high N/P ratios. What is needed in the art is a gene delivery system that uses a biodegradable, efficient and integrated natural polymer and has high transfection efficiency, long blood circulation and effective targeting properties.